tbuckley/cabot-search huggingface dataset:
American College of Rheumatology/EULAR remission criteria for rheumatoid arthritis: 2022 revision
Authors: Paul Studenic, Daniel Aletaha, Maarten de Wit, Tanja A Stamm, Farideh Alasti, Diane Lacaille, Josef S Smolen, David T Felson
Journal: Annals of the Rheumatic Diseases (2022)

In 2011, the American College of Rheumatology (ACR) and EULAR endorsed provisional criteria for remission in rheumatoid arthritis (RA), both Boolean-based and index-based. Based on recent studies indicating that a higher threshold for the patient global assessment (PtGA) may improve agreement between the two sets of criteria, our goals were to externally validate a revision of the Boolean remission criteria using a higher PtGA threshold and to validate the provisionally endorsed index-based criteria.We used data from four randomised trials comparing biological disease-modifying antirheumatic drugs to methotrexate or placebo. We tested the higher proposed PtGA threshold of 2 cm (Boolean2.0) (range 0-10 cm) compared with the original threshold of 1 cm (Boolean1.0). We analysed agreement between the Boolean-based and index-based criteria (Simplified Disease Activity Index (SDAI) and Clinical Disease Activity Index (CDAI)) for remission and examined how well each remission definition predicted later good physical function (Health Assessment Questionnaire (HAQ) score≤0.5) and radiographic non-progression.Data from 2048 trial participants, 1101 with early RA and 947 with established RA, were included. The proportion of patients with disease in remission at 6 months after treatment initiation increased when using Boolean2.0 compared with Boolean1.0, from 14.8% to 20.6% in early RA and 4.2% to 6.0% in established RA. Agreement between Boolean2.0 and the SDAI or CDAI remission criteria was better than for Boolean1.0, particularly in early disease. Boolean2.0, SDAI, and CDAI remission criteria had similar positive likelihood ratios (LRs) to predict radiographic nonprogression and a HAQ score of ≤0.5 (positive LR 3.8-4.3). The omission of PtGA (BooleanX) worsened the prediction of good functional outcomes.Using the Boolean 2.0 criteria classifies, more patients as achieving remission and increases the agreement with index-based remission criteria without jeopardising predictive value for radiographic or functional outcomes. This revised Boolean definition and the previously provisionally endorsed index-based criteria were endorsed by ACR and EULAR.
Environmental Health: A Position Paper From the American College of Physicians
Authors: Ryan Crowley, Suja Mathew, David Hilden, Suja Mathew, David Hilden, Micah Beachy, William Curry, Matthew Hollon, Cynthia A. Jumper, Pranav Mellacheruvu, Marianne C. Parshley, Ankita Sagar, Jamar Slocum, Michael Tan, Vanessa Van Doren, Elham A. Yousef
Journal: Annals of Internal Medicine (2022)

Environmental health refers to the health effects associated with environmental factors, such as air pollution, water contamination, and climate change. Environmental hazards are associated with poor outcomes in common diseases, including diabetes and heart disease. In this position paper, the American College of Physicians (ACP) seeks to inform physicians about environmental health and offers policymakers recommendations to reduce the adverse health consequences of climate change, improve air and water quality, reduce exposure to toxic substances, and address environmental injustice. ACP affirms that all communities, including people of color, people with low income, and marginalized populations, deserve to live in a healthy environment.
Autoreactive Plasmablasts After B Cell Depletion With Rituximab and Relapses in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis
Authors: Alvise Berti, Sophie Hillion, Maximilian F. Konig, Marta Casal Moura, Amber M. Hummel, Eva Carmona, Tobias Peikert, Fernando C. Fervenza, Cees G.M. Kallenberg, Carol A. Langford, Peter A. Merkel, Paul A. Monach, Philip Seo, Robert F. Spiera, Paul Brunetta, E. William St. Clair, Kristina M. Harris, John H. Stone, Guido Grandi, Jacques‐Olivier Pers, Ulrich Specks, Divi Cornec
Journal: Arthritis & Rheumatology (2022)

Autoreactive B cells are responsible for antineutrophil cytoplasmic antibody (ANCA) production in ANCA-associated vasculitis (AAV). Rituximab (RTX) depletes circulating B cells, including autoreactive B cells. We aimed to evaluate changes and associations with relapse of the circulating autoreactive B cell pool following therapeutic B cell depletion in AAV. Sequential flow cytometry was performed on 148 samples of peripheral blood mononuclear cells from 23 patients with proteinase 3 (PR3)-ANCA-positive AAV who were treated with RTX for remission induction and monitored after stopping therapy during long-term follow-up in a prospective clinical trial. PR3 was used as a ligand to target autoreactive PR3-specific (PR3+) B cells. B cell recurrence was considered as the first blood sample with ≥10 B cells/μl after RTX treatment. At B cell recurrence, PR3+ B cell frequency among B cells was higher than baseline (P < 0.01). Within both PR3+ and total B cells, frequencies of transitional and naive subsets were higher at B cell recurrence than at baseline, while memory subsets were lower (P < 0.001 for all comparisons). At B cell recurrence, frequencies of B cells and subsets did not differ between patients who experienced relapse and patients who remained in remission. In contrast, the plasmablast frequency within the PR3+ B cell pool was higher in patients who experienced relapse and associated with a shorter time to relapse. Frequencies of PR3+ plasmablasts higher than baseline were more likely to be found in patients who experienced relapse within the following 12 months compared to those in sustained remission (P < 0.05). The composition of the autoreactive B cell pool varies significantly following RTX treatment in AAV, and early plasmablast enrichment within the autoreactive pool is associated with future relapses.
Competing reasons, incomplete preferences, and framing effects
Authors: Richard Pettigrew
Journal: Behavioral and Brain Sciences (2022)

The quasi-cyclical preferences that Bermúdez ascribes to Agamemnon and others in analogous situations do not best represent them. I offer two alternative accounts. One works best if the preference ordering is taken to be the agent's personal betterness ordering of acts; the other works best if it is taken to provide a summary of the agent's dispositions to act.
A new LKB1 activator, piericidin analogue S14, retards renal fibrosis through promoting autophagy and mitochondrial homeostasis in renal tubular epithelial cells
Authors: Canzhen Liu, Xiaoxu Wang, Xiaonan Wang, Yunfang Zhang, Wenjian Min, Ping Yu, Jinhua Miao, Weiwei Shen, Shuangqin Chen, Shan Zhou, Xiaolong Li, Ping Meng, Qinyu Wu, Fan Fan Hou, Youhua Liu, Peng Yang, Cheng Wang, Xu Lin, Lan Tang, Xuefeng Zhou, Lili Zhou
Journal: Theranostics (2022)

Background: Liver kinase B1 (LKB1) is the key regulator of energy metabolism and cell homeostasis.LKB1 dysfunction plays a key role in renal fibrosis.However, LKB1 activators are scarce in commercial nowadays.This study aims to discover a new drug molecule, piericidin analogue S14 (PA-S14), preventing renal fibrosis as a novel activator to LKB1.Methods: Our group isolated PA-S14 from the broth culture of a marine-derived Streptomyces strain and identified its binding site.We adopted various CKD models or AKI-CKD model (5/6 nephrectomy, UUO, UIRI and adriamycin nephropathy models).TGF-β-stimulated renal tubular cell culture was also tested.Results: We identified that PA-S14 binds with residue D176 in the kinase domain of LKB1, and then induces the activation of LKB1 through its phosphorylation and complex formation with MO25 and STRAD.As a result, PA-S14 promotes AMPK activation, triggers autophagosome maturation, and increases autophagic flux.PA-S14 inhibited tubular cell senescence and retarded fibrogenesis through activation of LKB1/AMPK signaling.Transcriptomics sequencing and mutation analysis further demonstrated our results.Conclusion: PA-S14 is a novel leading compound of LKB1 activator.PA-S14 is a therapeutic potential to renal fibrosis through LKB1/AMPK-mediated autophagy and mitochondrial homeostasis pathways.
A novel afterglow nanoreporter for monitoring cancer therapy
Authors: Shiyi Liao, Youjuan Wang, Zhe Li, Ying Zhang, Xia Yin, Shuangyan Huan, Xiao-Bing Zhang, Sulai Liu, Guosheng Song
Journal: Theranostics (2022)

Rationale: Immunogenic cell death (ICD)-associated immunogenicity evoked through reactive oxygen species (ROS) is an efficient way to fight against the immune-dysfunctional microenvironment, so as to provoke potent anti-tumor immunity.However, the unknown ROS dose during cancer therapies may induce adverse immune responses (e.g., insufficient ICD, toxicity toward normal tissues or immune system).Methods: Herein, we developed a pyrido pyrazine -thiophene based semiconducting polymer as novel near-infrared (NIR) organic afterglow nanoparticles for the real-time visualization of self-generated ROS, during photodynamic-mediated immunogenic cell death.Specifically, we introduced the strong "acceptor" (pyrido pyrazine) into thiophene based semiconducting polymer to redshift emission wavelength, and further modulate the "donor" to afford more afterglow reaction sites and reducing ΔEst, so as to enhance luminescence intensity.Results: The semiconducting polymer-based afterglow nanoparticles exhibit strong afterglow emission with longer-wavelength emission (> 800 nm), compared with the reported organic afterglow nanoparticles (e.g., MEHPPV, PFODBT or Chlorin, < 690 nm), which endows this afterglow nanoparticles with a greatly improvement of signal to noise ratio.Moreover, the photodynamic effect of this afterglow nanoparticles can induce immunogenic cell death of cancer cells and further cause immune responses in mice. Conclusions:The NIR afterglow signal presents a good relationship with ROS generation, immunogenic cell death and outcome of treatment.Therefore, it was able to provide a non-invasive tool for predicting the degree of ICD that occurs during ROS-mediated cancer therapy and may contribute to precise immunotherapy.
Artificial intelligence in pancreatic cancer
Authors: Bowen Huang, Haoran Huang, Shuting Zhang, Dingyue Zhang, Qingya Shi, Jianzhou Liu, Junchao Guo
Journal: Theranostics (2022)

Pancreatic cancer is the deadliest disease, with a five-year overall survival rate of just 11%.The pancreatic cancer patients diagnosed with early screening have a median overall survival of nearly ten years, compared with 1.5 years for those not diagnosed with early screening.Therefore, early diagnosis and early treatment of pancreatic cancer are particularly critical.However, as a rare disease, the general screening cost of pancreatic cancer is high, the accuracy of existing tumor markers is not enough, and the efficacy of treatment methods is not exact.In terms of early diagnosis, artificial intelligence technology can quickly locate high-risk groups through medical images, pathological examination, biomarkers, and other aspects, then screening pancreatic cancer lesions early.At the same time, the artificial intelligence algorithm can also be used to predict the survival time, recurrence risk, metastasis, and therapy response which could affect the prognosis.In addition, artificial intelligence is widely used in pancreatic cancer health records, estimating medical imaging parameters, developing computer-aided diagnosis systems, etc. Advances in AI applications for pancreatic cancer will require a concerted effort among clinicians, basic scientists, statisticians, and engineers.Although it has some limitations, it will play an essential role in overcoming pancreatic cancer in the foreseeable future due to its mighty computing power.
Distinguishing nanoparticle drug release mechanisms by asymmetric flow field–flow fractionation
Authors: Sheyda Shakiba, Saba Shariati, Haoran Wu, Carlos E. Astete, Rafael Cueto, Elham H. Fini, Debora F. Rodrigues, Cristina M. Sabliov, Stacey M. Louie
Journal: Journal of Controlled Release (2022)
Combination of the STING Agonist MIW815 (ADU-S100) and PD-1 Inhibitor Spartalizumab in Advanced/Metastatic Solid Tumors or Lymphomas: An Open-Label, Multicenter, Phase Ib Study
Authors: Funda Meric-Bernstam, Randy F. Sweis, Stefan Kasper, Omid Hamid, Shailender Bhatia, Reinhard Dummer, Agostina Stradella, Georgina V. Long, Anna Spreafico, Toshio Shimizu, Neeltje Steeghs, Jason J. Luke, Sarah M. McWhirter, Thomas Müller, Nitya Nair, Nancy Lewis, Xinhui Chen, Andrew Bean, Lisa Kattenhorn, Marc Pelletier, Shahneen Sandhu
Journal: Clinical Cancer Research (2022)

Abstract Purpose: The stimulator of IFN genes (STING) is a transmembrane protein that plays a role in the immune response to tumors. Single-agent STING agonist MIW815 (ADU-S100) has demonstrated immune activation but limited antitumor activity. This phase Ib, multicenter, dose-escalation study assessed the safety and tolerability of MIW815 plus spartalizumab (PDR001), a humanized IgG4 antibody against PD-1, in 106 patients with advanced solid tumors or lymphomas. Patients and Methods: Patients were treated with weekly intratumoral injections of MIW815 (50–3,200 μg) on a 3-weeks-on/1-week-off schedule or once every 4 weeks, plus a fixed dose of spartalizumab (400 mg) intravenously every 4 weeks. Results: Common adverse events were pyrexia (n = 23; 22%), injection site pain (n = 21; 20%), and diarrhea (n = 12; 11%). Overall response rate was 10.4%. The MTD was not reached. Pharmacodynamic biomarker analysis demonstrated on-target activity. Conclusions: The combination of MIW815 and spartalizumab was well tolerated in patients with advanced/metastatic cancers, including in patients with anti-PD-1 refractory disease. Minimal antitumor responses were seen.
CUB Domain-Containing Protein 1 (CDCP1) is a rational target for the development of imaging tracers and antibody-drug conjugates for cancer detection and therapy
Authors: Tashbib Khan, Nicholas J. Lyons, Madeline Gough, Kayden K.X. Kwah, Tahleesa J. Cuda, Cameron E. Snell, Brian W. Tse, Kamil A. Sokolowski, Lesley A. Pearce, Timothy E. Adams, Stephen E. Rose, Simon Puttick, Marina Pajic, Mark N. Adams, Yaowu He, John D. Hooper, Thomas Kryza
Journal: Theranostics (2022)

Rationale: An antibody-drug conjugate (ADC) is a targeted therapy consisting of a cytotoxic payload that is linked to an antibody which targets a protein enriched on malignant cells.Multiple ADCs are currently used clinically as anti-cancer agents significantly improving patient survival.Herein, we evaluated the rationale of targeting the cell surface oncoreceptor CUB domain-containing protein 1 (CDCP1) using ADCs and assessed the efficacy of CDCP1-directed ADCs against a range of malignant tumors.Methods: CDCP1 mRNA expression was evaluated using large transcriptomic datasets of normal/tumor samples for 23 types of cancer and 15 other normal organs, and CDCP1 protein expression was examined in 34 normal tissues, >300 samples from six types of cancer, and in 49 cancer cell lines.A recombinant human/mouse chimeric anti-CDCP1 antibody (ch10D7) was labelled with 89 Zirconium or monomethyl auristatin E (MMAE) and tested in multiple pre-clinical cancer models including 36 cancer cell lines and three mouse xenograft models.Results: Analysis of CDCP1 expression indicates elevated CDCP1 expression in the majority of the cancers and restricted expression in normal human tissues.Antibody ch10D7 demonstrates a high affinity and specificity for CDCP1 inducing cell signalling via Src accompanied by rapid internalization of ch10D7/CDCP1 complexes in cancer cells. 89Zirconium-labelled ch10D7 accumulates in CDCP1 expressing cells enabling detection of pancreatic cancer xenografts in mice by PET imaging.Cytotoxicity of MMAE-labelled ch10D7 against kidney, colorectal, lung, ovarian, pancreatic and prostate cancer cells in vitro, correlates with the level of CDCP1 on the plasma membrane.ch10D7-MMAE displays robust anti-tumor effects against mouse xenograft models of pancreatic, colorectal and ovarian cancer.Conclusion: CDCP1 directed imaging agents will be useful for selecting cancer patients for personalized treatment with cytotoxin-loaded CDCP1 targeting agents including antibody-drug conjugates.
Near-infrared photoimmunotherapy: design and potential applications for cancer treatment and beyond
Authors: Danfeng Wei, Jinxin Qi, Michael R Hamblin, Xiang Wen, Xian Jiang, Hao Yang
Journal: Theranostics (2022)

Near-infrared photoimmunotherapy (NIR-PIT) is a newly developed cancer treatment modality based on a target-specific photosensitizer conjugate (TSPC) composed of an NIR phthalocyanine photosensitizer and an antigen-specific recognition system.NIR-PIT has predominantly been used for targeted therapy of tumors via local irradiation with NIR light, following binding of TSPC to antigen-expressing cells.Physical stress-induced membrane damage is thought to be a major mechanism underlying NIR-PIT-triggered photokilling.Notably, NIR-PIT can rapidly induce immunogenic cell death and activate the adaptive immune response, thereby enabling its combination with immune checkpoint inhibitors.Furthermore, NIR-PIT-triggered "super-enhanced permeability and retention" effects can enhance drug delivery into tumors.Supported by its potential efficacy and safety, NIR-PIT is a rapidly developing therapeutic option for various cancers.Hence, this review seeks to provide an update on the (i) broad range of target molecules suitable for NIR-PIT, (ii) various types of receptor-selective ligands for designing the TSPC "magic bullet," (iii) NIR light parameters, and (iv) strategies for enhancing the efficacy of NIR-PIT.Moreover, we review the potential application of NIR-PIT, including the specific design and efficacy in 19 different cancer types, and its clinical studies.Finally, we summarize possible NIR-PIT applications in noncancerous conditions, including infection, pain, itching, metabolic disease, autoimmune disease, and tissue engineering.
Three Distinct Transcriptional Profiles of Monocytes Associate with Disease Activity in Scleroderma Patients
Authors: Hadijat‐Kubura M. Makinde, Julia L. M. Dunn, Gaurav Gadhvi, Mary Carns, Kathleen Aren, Anh H. Chung, Lutfiyya N. Muhammad, Jing Song, Carla M. Cuda, Salina Dominguez, John E. Pandolfino, Jane E. Dematte D'Amico, G. Scott Budinger, Shervin Assassi, Tracy M. Frech, Dinesh Khanna, Alex Shaeffer, Harris Perlman, Monique Hinchcliff, Deborah R. Winter
Journal: Arthritis & Rheumatology (2022)

Objective Patients with diffuse cutaneous systemic sclerosis (dcSSc) display a complex clinical phenotype. Transcriptional profiling of whole blood or tissue from patients are affected by changes in cellular composition that drive gene expression and an inability to detect minority cell populations. We undertook this study to focus on the 2 main subtypes of circulating monocytes, classical monocytes (CMs) and nonclassical monocytes (NCMs) as a biomarker of SSc disease severity. Methods SSc patients were recruited from the Prospective Registry for Early Systemic Sclerosis. Clinical data were collected, as well as peripheral blood for isolation of CMs and NCMs. Age‐, sex‐, and race‐matched healthy volunteers were recruited as controls. Bulk macrophages were isolated from the skin in a separate cohort. All samples were assayed by RNA sequencing (RNA‐seq). Results We used an unbiased approach to cluster patients into 3 groups (groups A–C) based on the transcriptional signatures of CMs relative to controls. Each group maintained their characteristic transcriptional signature in NCMs. Genes up‐regulated in group C demonstrated the highest expression compared to the other groups in SSc skin macrophages, relative to controls. Patients from groups B and C exhibited worse lung function than group A, although there was no difference in SSc skin disease at baseline, relative to controls. We validated our approach by applying our group classifications to published bulk monocyte RNA‐seq data from SSc patients, and we found that patients without skin disease were most likely to be classified as group A. Conclusion We are the first to show that transcriptional signatures of CMs and NCMs can be used to unbiasedly stratify SSc patients and correlate with disease activity outcome measures.
Targeting PI4KA sensitizes refractory leukemia to chemotherapy by modulating the ERK/AMPK/OXPHOS axis
Authors: Xiuxing Jiang, Xiangtao Huang, Guoxun Zheng, Guanfei Jia, Zhiqiang Li, Xin Ding, Ling Lei, Liang Yuan, Shuangnian Xu, Ning Gao
Journal: Theranostics (2022)

Background: The emergence of chemoresistance in leukemia markedly impedes chemotherapeutic efficacy and dictates poor prognosis. Recent evidence has revealed that phosphatidylinositol 4 kinase-IIIα (PI4KA) plays a critical role in tumorigenesis. However, the molecular mechanisms of PI4KA-regulated chemoresistance and leukemogenesis remain largely unknown. Methods: Liquid chromatography-mass spectrometry (LC-MS), patient samples and leukemia xenograft mouse models were used to investigate whether PI4KA was an effective target to overcome chemoresistance in leukemia. Enzyme-linked immunosorbent assay (ELISA) and molecular mechanics/generalized born surface area (MM/GBSA) method were employed to identify cepharanthine (CEP) as a novel PI4KA inhibitor. Results: High expression of PI4KA was observed in drug-resistant leukemia cells or in relapsed leukemia patients, which was correlated with poor overall survival. Depletion of PI4KA sensitized drug-resistant leukemia cells to chemotherapeutic drugs in vitro and in vivo by regulating ERK/AMPK/OXPHOS axis. We also identified cepharanthine (CEP) as a novel PI4KA inhibitor, which could undermine the stability of the PI4KA/TTC7/FAM126 complex, enhancing the sensitivity of drug-resistant leukemia cells to chemotherapeutic drugs in vitro and in vivo. Conclusions: Our study underscored the potential of therapeutic targeting of PI4KA to overcome chemoresistance in leukemia. A combination of the PI4KA inhibitor with classic chemotherapeutic agents could represent a novel therapeutic strategy for the treatment of refractory leukemia.